A humanized BAC transgenic/knockout mouse model for HbE/β-thalassemia

Hemoglobin E (HbE) is caused by a G→A mutation at codon 26 of the β-globin gene, which substitutes Glu→Lys. This mutation gives rise to functional but unstable hemoglobin and activates a cryptic splice site causing mild anemia. HbE reaches a carrier frequency of 60–80% in some Southeast Asian populations. HbE causes serious disease when co-inherited with a β-thalassemia mutation. In this study, we report the creation and evaluation of humanized transgenic mice containing the βE mutation in the context of the human β-globin locus. Developmental expression of the human βE locus transgene partially complements the hematological abnormalities in heterozygous knockout mice (muβth-3/+) and rescues the embryonic lethality of homozygous knockout mice (muβth-3/th-3). The phenotype of rescued mice was dependent on the transgene copy number. This mouse model displays hematological abnormalities similar to HbE/β-thalassemia patients and represent an ideal in vivo model system for pathophysiological studies and evaluation of novel therapies.